Angiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway (Zetter, B. R., Annu Rev Med, 49: 407-424 (1998)). Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs.
In addition, angiogenesis has been associated with blood-born tumors such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.
Excessive angiogenesis or abnormal growth of new blood vessels has also contributed to a variety of other diseases or conditions that are commonly known in the art to be associated with or otherwise mediated by angiogenesis. One such example is ocular neovascular disease. This disease is characterized by invasion of new blood vessels into the structures of the eye such as the retina or cornea. In age-related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasias. Other diseases or medical conditions associated with angiogenesis known in the art include, but without limitation to, rheumatoid arthritis, systemic lupus, polyarteritis, sickle cell anemia, osteoarthritis, vein occlusion, artery occlusion, carotid obstructive disease and atherosclerosis. Therapies directed at control of the angiogenic process could lead to the abrogation or mitigation of these diseases and conditions. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents (U.S. Pat. No. 6,518,298).
ST104P {(tetrameric cyclic compound of 4,5-dihydroxynaphthalene-2,7, disulfonic acid linked by methylene bridges (Poh B.-L., et al, Tetra. Letters 30(8):1005-1008 (1989), Poh, B.-L., and Lim, C. S., Tetrahedron 46(10):3651-3658 (1990a), and Poh, B.-L., et al, Tetrahedron 46(12):4679-4386 (1990b)) is a synthetic polysulfated-, cyclo-, tetrachromotropylene macrocyclic compound containing four naphthalene units in its cyclic structure. It is a water-soluble compound with marginal cellular toxicity. The functions of ST104P as anti-viral agents and anti-thrombotic treatment have been indicated in previous studies (U.S. Pat. Nos. 5,166,173, 5,196,452, 5,312,837, 5,441,983 and 5,409,959). However, ST104P has never been indicated to be an anti-angiogenic agent exhibiting anti-angiogenic functions useful for treatment of various diseases or conditions caused by or in association with undesirable angiogenesis including, but not limited to, cancer therapy.
It is theoretically possible that a compound exhibiting anti-viral and anti-thrombotic activity may also possess other biological activities either by a similar or an entirely different mechanism. It is therefore an object of the present invention to provide for a composition comprising ST104P exhibiting a remarkable anti-angiogenic activity suitable for cancer therapy.
It is a further object of the invention to provide for a method of providing therapeutical benefits for a human patient in cancer therapy employing a composition comprising ST104P
It is a further object of the invention to provide for a composition comprising ST104P exhibiting a remarkable activity against diseases or conditions mediated by or in connection with angiogenesis including, without limitation, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, osteoarthritis, atherosclerosis, corneal neovascularization, retinal/choroidal neovascularization and systemic lupus.